This PPG was started in September, 1982. The central theme is "the study of the role of vasoactive systems (autocrine, juxtacrine, paracrine and endocrine) in the regulation of renal function and blood pressure (BP) and mediation of target organ damage". The general hypothesis to be tested is that there is a balance between systems that promote water and sodium retention, hypertension and target organ damage (Ang II, COX-2 products and free radicals), and systems that antagonize these effects (kinins, NO, Ac-SDKP and activation of the Ang II type 2 receptor). Alterations of this balance in favor of the former are responsible for the development of hypertension and target organ damage, while alterations of this balance in favor of the latter have therapeutic effects. We will use molecular, physiological, and pharmacological approaches to study vasoactive systems at the subcellular, cellular, and isolated organ levels and in intact animals in both acute and chronic models, including transgenic mice. In project 1 we will study whether a novel peptide (Ac-SDKP) alters the balance between systems that promote and oppose target organ damage in favor of the latter, thus preventing and regressing this process. In project 2 we will study whether the local effects of Ang II in the heart are antagonized by activation of the AT2 receptor, kinins and NO. In project 3 we will study whether COX-2 via EP1 and EP3 receptors promotes the development of cardiovascular disease and whether this effect is antagonized by the PPAR receptor. In project 4 we will study the regulation of renal microcirculation by the juxtaglomerular apparatus to see whether there is an interplay between vasodepressor autacoids (NO, kinins and vasodilator eicosanoids) and vasopressor systems (Ang II, reactive oxygen species and cP450 vasoconstrictor metabolites). In project 5 we will study whether NO produced by eNOS in the renal tubules alters the water and sodium balance in favor of natriuresis and diuresis, thus opposing hypertensive stimuli. Four core units (Administrative, Analytical and Morphology, Mutant Mouse, Biostatistics) will support and facilitate the scientific efforts of the investigators. Special expertise is centralized in the cores so that resources can be used more efficiently. The Program Project provides integration of our efforts, continuing collaboration and sharing of ideas and expertise; thus it accelerates acquisition of knowledge on the pathogenesis of hypertension and target organ damage.